title: Deletion of the first cysteine-rich region of the varicella-zoster virus glycoprotein E ectodomain abolishes the gE and gI interaction and differentially affects cell-cell spread and viral entry.
abstract: Varicella-zoster virus (VZV) glycoprotein E (gE) is the most abundant glycoprotein in infected cells and, in contrast to those of other alphaherpesviruses, is essential for viral replication. The gE ectodomain contains a unique N-terminal region required for viral replication, cell-cell spread, and secondary envelopment; this region also binds to the insulin-degrading enzyme (IDE), a proposed VZV receptor. To identify new functional domains of the gE ectodomain, the effect of mutagenesis of the first cysteine-rich region of the gE ectodomain (amino acids 208 to 236) was assessed using VZV cosmids. Deletion of this region was compatible with VZV replication in vitro, but cell-cell spread of the rOka-DeltaCys mutant was reduced significantly. Deletion of the cysteine-rich region abolished the binding of the mutant gE to gI but not to IDE. Preventing gE binding to gI altered the pattern of gE expression at the plasma membrane of infected cells and the posttranslational maturation of gI and its incorporation into viral particles. In contrast, deletion of the first cysteine-rich region did not affect viral entry into human tonsil T cells in vitro or into melanoma cells infected with cell-free VZV. These experiments demonstrate that gE/gI heterodimer formation is essential for efficient cell-cell spread and incorporation of gI into viral particles but that it is dispensable for infectious varicella-zoster virion formation and entry into target cells. Blocking gE binding to gI resulted in severe impairment of VZV infection of human skin xenografts in SCIDhu mice in vivo, documenting the importance of cell fusion mediated by this complex for VZV virulence in skin.
authors.affiliation: Institut Pasteur, Départment de Virologie, 25 rue du Dr Roux, 75015 Paris, France. barbara.berarducci@pasteur.fr
authors.forename: Barbara
authors.initials: B
authors.lastname: Berarducci
authors.forename: Jaya
authors.initials: J
authors.lastname: Rajamani
authors.forename: Mike
authors.initials: M
authors.lastname: Reichelt
authors.forename: Marvin
authors.initials: M
authors.lastname: Sommer
authors.forename: Leigh
authors.initials: L
authors.lastname: Zerboni
authors.forename: Ann M
authors.initials: AM
authors.lastname: Arvin
mesh_terms: D000818:Animals; D002460:Cell Line; D006562:Herpes Zoster; D014645:Herpesvirus 3, Human / Q000472:pathogenicity* / Q000502:physiology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D011485:Protein Binding; D017384:Sequence Deletion; D014183:Transplantation, Heterologous; D014759:Viral Envelope Proteins / Q000235:genetics* / Q000378:metabolism*; D014774:Virulence; D019065:Virus Assembly; D053586:Virus Internalization
chemical_list: D014759:Viral Envelope Proteins; C056913:glycoprotein E, varicella-zoster virus